ABSTRACT FINAL ID: 1845
TITLE: Exploring Optimal Dosing Of Lonafarnib With Ritonavir For The Treatment Of Chronic Delta Hepatitis—Interim Results From The Lowr Hdv-2 Study.
SPONSORSHIP - THIS STUDY WAS SPONSORED BY: (IF THIS ABSTRACT WAS NOT SPONSORED PLEASE INDICATE):
This study was sponsored by Eiger Biopharma
Background/Aims: Lonafarnib (LNF) is an oral prenylation inhibitor with demonstrated efficacy in patients infected with hepatitis delta virus (HDV). This class of agents is known to be associated with gastrointestinal side effects. Results of the LOnafarnib With Ritonavir for HDV (LOWR HDV-1) study demonstrated that co-administering LNF with ritonavir (RTV), an inhibitor of LNF metabolism, increases the post-absorption levels of LNF, yielding greater efficacy with lower LNF doses compared to LNF monotherapy. The aim of LOWR HDV-2, a phase 2 dose-finding study, is to identify optimal combination regimens of LNF and RTV± PEG-IFNα with efficacy and tolerability for longer term dosing to induce clinically meaningful reductions in HDV RNA or enable HDV RNA clearance. Methods: 38 patients to date have been enrolled in 10 groups of decreasing doses of LNF in combination with RTV±PEG-IFNα for 12 or 24 wks. Groups were divided into high dose LNF (≥75mg bid) and low dose LNF (≤50mg bid). High dose groups (12 wks): LNF 100mg bid/RTV 100mg qd, n=3; LNF 100mg bid/RTV 50mg bid, n=2; LNF 100mg qd/RTV 100mg qd, n=5; LNF 150mg qd/RTV 100mg qd, n=3; LNF 75mg bid/RTV 100mg bid, n=3. Low dose groups (24 wks): LNF 50mg bid/RTV 100mg bid, n=3; LNF 50mg bid/RTV 100mg bid/PEG-IFNα180mcg qw, n=3; LNF 50mg bid/RTV 100mg bid, with addition of PEG-IFNα180mcg qw at 12 wks, n=4; LNF 25mg bid/RTV 100mg bid, n=5; LNF 25mg bid/RTV 100mg bid/PEG-IFNα
180mcg qw, n=7. Biochemical parameters and quantitative serum HDV-RNA viral loads (VL) were measured. To date, data from 33 of 38 subjects who have completed at least 12 wks of therapy was available for analysis. Results: There were significant GI-related side effects in the high dose groups, whereas the low dose groups exhibited good tolerability. Interim results reveal 16 of 27 (60%) subjects with baseline high ALT have normalized ALT at wk 12. Mean VL declines at wk 12 with the LNF high dose groups was -1.66 log IU/mL (range -0.08 to -3.94) compared to the low dose groups’ mean of -2.59 log IU/mL (range +0.21 to -6.91). In the low dose groups, 7/19 (37%) became HDV-RNA negative, with 13/19 (68%) demonstrating HDV-RNA declines of greater than 2 logs at wk 12. Conclusion: Treatment with LNF/RTV led to early decline in HDV-RNA in all patients. Low doses of LNF induced greater HDV-RNA VL declines compared to higher doses, likely due to better tolerability resulting in improved hepatic drug exposure. The majority of low dose patients have demonstrated HDV-RNA declines of greater than 2 logs at wk 12, and over a third have already become HDV-RNA negative to date. These data support longer duration studies of low-dose LNF-based combinations.